Immuno-oncology has revolutionized the treatment of melanoma and non-small-cell lung cancer (NSCLC), and shows promise for several other tumor types. At ASCO 2017, a substantial body of research has added to our understanding of these agents, with data from studies investigating approved agents helping clinicians select the best therapies from this class of treatments; and data from earlier-phase studies showing that there is potential for further expansion of immuno-oncology into other tumor types.

This summary provides the highlights of new research with immuno-oncologic agents in NSCLC, melanoma and urothelial cancer, and provides some commentary discussing the implications of these findings.

Immuno-oncology in Non-small Cell Lung Cancer (NSCLC)

The primary results of monotherapy trials involving pembrolizumab (KEYNOTE-024) and nivolumab (CHECKMATE-026) were initially presented at ESMO 2016.1-3 In KEYNOTE-024, which has been published in the New England Journal of Medicine, pembrolizumab was found to be superior to chemotherapy in terms of progression-free survival (PFS) and overall survival (OS) among patients with PD-L1 expression in ≥ 50% of tumor cells.1,2 The median follow-up for this primary analysis was 11.2 months.1,2 Conversely, CHECKMATE-026, which used a PD-L1 expression cut-off threshold of ≥ 5%, failed to demonstrate a significant difference between nivolumab and chemotherapy in terms of either PFS or OS.3

At ASCO 2017, researchers presented an update of important endpoint information from the KEYNOTE-024 trial.4 The median duration of follow-up for this data set was 19.1 months. At the time of data cutoff (January 5th, 2017), there were 46 patients continuing on pembrolizumab (of the 154 originally randomized and treated in that arm) and 1 patient continuing on chemotherapy (of the 150 originally randomized and treated in that arm). Ninety-seven patients from the original chemotherapy arm received any subsequent therapy. Of these, 79 patients (81.4%) in the chemotherapy group had crossed over to pembrolizumab, and a further 12 patients (12.4%) received a PD-1 inhibitor outside of the crossover protocol. For this updated analysis, median OS was 14.5 months in the chemotherapy arm and still not reached in the pembrolizumab arm (HR 0.63; p = 0.003; Figure 1). The 12-month and 18-month OS rates were 70.3% and 61.2% for pembrolizumab, respectively and 54.8% and 43.0% for chemotherapy, respectively.

The investigators also examined progression-free survival in the second line (PFS2) for this updated analysis. This metric is defined as “time from randomization to objective tumor progression on next-line treatment or death from any cause, whichever occurs first.” Of the 154 patients in the pembrolizumab arm, 48 (31%) received any subsequent therapy (42 of whom [27% of the pembrolizumab arm] received a platinum-based doublet). In the chemotherapy arm, 97 patients (64%) received a subsequent therapy (91 of whom [60% of the chemotherapy arm] received a PD-1 inhibitor). As shown in Figure 2, PFS2 was significantly longer with pembrolizumab (median 18.3 months) than with chemotherapy (median 8.4 months) (HR 0.54; p < 0.001). The continued separation of the curves for PFS2 reinforces the appropriateness of the sequence of starting with PD-1 inhibition and then proceeding to chemotherapy in the event of a failure, rather than the reverse order. The authors concluded that these data “support the use of pembrolizumab as standard of care for first-line treatment of NSCLC with PD-L1 TPS ≥ 50%.”

Pembrolizumab also has been evaluated in combination with chemotherapy (carboplatin + pemetrexed) vs. chemotherapy alone as first-line therapy for non-squamous NSCLC (the phase 1/2 KEYNOTE-021 study).6 Note that in this study, although patients provided biopsy samples for PD-L1 assessment, this was an “all-comer” trial, with no specific PD-L1 threshold required for entry. Updated results presented at ASCO 2017 showed that, over a median follow-up of 14.5 months, the risk of progression or death was 50% lower in the pembrolizumab + chemotherapy arm (n = 60) compared to chemotherapy alone (n = 63) (HR 0.50; p = 0.0038).6 There also was numerically (not statistically significantly) improved survival (12-month OS 76% vs. 69%, respectively; HR 0.69; p = 0.13). The utility of pembrolizumab + chemotherapy is being further explored in a phase 3 study, KEYNOTE-189.7

Other research presented in first-line treatment of NSCLC included a two-year update of OS from the CHECKMATE-012 study, in which patients were treated with a combination of nivolumab and the CTLA-4 inhibitor, ipilimumab.8 Among the 77 patients treated with the combination, the median follow-up for this updated analysis was 20 months. During this time, the nivolumab + ipilimumab combination continued to demonstrate clinical benefit, with a two-year OS rate of 49% (58% among the 47 patients with a PD-L1 expression ≥ 1%). Importantly, a subset of patients (n = 14) who discontinued nivolumab + ipilimumab had sustained responses in the absence of therapy.

Also at ASCO 2017, researchers presented updated data for pembrolizumab use among a combined phase 1b cohort, including previously treated (n = 449) and treatment-naïve (n = 101) individuals with advanced NSCLC (KEYNOTE-001).9 The three-year OS, in this updated analysis, was 26.4% among those who were previously untreated and 19% among previously treated patients. No new safety signals emerged out of the three years of follow-up.

Pembrolizumab also has been evaluated in combination with the investigational agent, epacadostat (an IDO1 enzyme inhibitor), in a phase 1/2 study across multiple tumor types (ECHO-202/KEYNOTE-037).10 Fifty-eight patients with NSCLC have been enrolled, and preliminary response findings were available for 40 patients for the analysis presented at ASCO 2017. The overall ORR was 35% (14/40).

Other interesting research with immuno-oncology agents in previously treated NSCLC patients come from an analysis of treatment beyond disease progression with the PD-L1 inhibitor, atezolizumab, in the OAK study.11 The OAK trial protocol allowed for treatment with atezolizumab beyond progression (as per RECIST 1.1 criteria), as long as patients were experiencing clinical benefit. Among the 425 patients randomized to atezolizumab therapy, 332 progressed. Of these, 168 (51%) continued atezolizumab, 94 (28%) were treated with other anti-cancer therapy (including seven who received another immunotherapy) and 70 (21%) received no subsequent therapy. In the docetaxel arm (n = 425), 290 patients progressed. Of these, 167 received another anti-cancer treatment, including 65 who received an immunotherapy. As shown in Figure 3, among patients who progressed in the atezolizumab treatment arm, OS was longer among those who continued with atezolizumab post progression (median OS 12.7 months) vs. other anti-cancer therapy (median 8.8 months) or no treatment (median 2.2 months). The 18-month OS rates were 37% for atezolizumab, 20% for other anti-cancer therapy and 9% for no treatment. Among those who progressed in the docetaxel arm, OS was longer for those who switched to an immunotherapy (median OS 17.3 months) compared to a non-immunotherapy treatment (median 7.5 months) or no treatment (median 3.7 months).

EXPERT COMMENTARY - DR. QUINCY CHU
The update of KEYNOTE-024 confirmed the survival benefit of first-line pembrolizumab in the subset of NSCLC patients whose tumors expressed PD-L1 ≥ 50%. The sequence of pembrolizumab followed by chemotherapy yielded superior survival than the reverse sequence. Thus, PD-L1 testing in newly diagnosed metastatic NSCLC needs to be implemented. The clinical benefits from pembrolizumab/chemotherapy in the non-squamous NSCLC, IDO/pembrolizumab and ipilimumab/nivolumab in all NSCLC with any level of PD-L1 expression were promising. The main questions to be answered include 1) who will benefit the most from these combinations (PD-L1 0% vs. PD-L1 1-49% vs. PD-L1 ≥ 50%)? and 2) will the toxicity from these combinations be worth the gains in survival? The soon-to-be-reported KEYNOTE-189 and CHECKMATE-227 will provide some answers to these questions.

Although there was a survival benefit from treatment beyond progression with atezolizumab, this may not be applicable to all patients in the clinic as the clinical characteristics of these patients were not presented. One would postulate that patients who have RECIST progression without any new/progressed symptoms, those who have progression or develop one or two new lesions, those who have progression in the brain alone or those who have nodal progression in the setting of infection may benefit the most from treatment beyond progression. Stringent follow-up and documentation of symptoms need to be implemented so that patients can still be offered subsequent therapy before their performance status deteriorates significantly.

Immuno-oncology in Melanoma

The most eagerly anticipated data for the management of previously untreated melanoma had been the OS data from the CHECKMATE-067 study designed to compare the PD-1 inhibitor, nivolumab (alone or in combination with the CTLA-4 inhibitor, ipilimumab) to ipilimumab alone.12 Although the updated data, presented at AACR 2017, did show a numerical (not statistically significant) 5% OS advantage at two years for the combination compared with nivolumab monotherapy,13 there continues to be debate regarding whether these modest surival benefits merit the use of this highly toxic combination, or whether single-agent PD-1 inhibition is a more appealing choice.

With respect to the latter strategy, the ASCO 2017 program included some updated data on single-agent anti-PD-1 therapy. The phase 3 KEYNOTE-006 study randomized 834 ipilimumab-naïve patients to pembrolizumab every two weeks or every three weeks (each for two years); or ipilimumab 3 mg/kg every three weeks for four doses.14 The updated data presented at ASCO were for a median follow-up of 33.9 months. Median OS was significantly higher for pembrolizumab compared to ipilimumab (32.3 months vs. 15.9 months, respectively). At the median follow-up time, the proportion of subjects surviving was 50% for pembrolizumab and 39% for ipilimumab (Figure 4). The median PFS was 8.3 months with pembrolizumab and 3.3 months with ipilimumab. For subjects who completed two years of pembrolizumab treatment (n = 104), the PFS rate at a median follow-up of 9.7 months after completing treatment was 91% (Figure 5), and 98% of patients were alive. This last point provides reassurance that it is indeed feasible to stop this therapy after two years and maintain durable efficacy after treatment cessation. The updated results also reinforced the known safety profile of single-agent pembrolizumab, with no new safety signals. The frequency of treatment-related grade 3/4 AEs was 17% in the pembrolizumab group and 19% in the ipilimumab group. AE-related treatment discontinuation occurred in 10% of subjects in the pembrolizumab group and 9% of those in the ipilimumab group. There was one AE-related death in the pembrolizumab group (sepsis).14

There were also some real-life data presented for pembrolizumab. Among 509 patients treated with pembrolizumab at 10 European hospitals, it was reported that two-thirds (67%) had stopped therapy due to progressive disease and 110 (22%) had stopped without PD (patient or physician decision [16%] or due to an AE [6%]).15 The investigators reported that those who stopped due to patient or physician decision were at low risk for short-term progression, irrespective of their best tumor response. However, those who stopped due to an AE (in the absence of PD) seemed to have a higher risk for subsequent progression. The authors attributed this to a shorter exposure to pembrolizumab in the latter group, as well as a longer follow-up after discontinuation. These real-world data help to confirm the findings of KEYNOTE-006 mentioned above, in terms of maintained response after stopping pembrolizumab.15

There were two studies evaluating the combination of nivolumab + ipilimumab among melanoma patients with brain metastases.16,17 One of these was the CHECKMATE-204 study, which enrolled 109 patients with at least one measurable brain met (0.5-3.0 cm) with no history of prior immuno-oncology treatment (prior BRAF inhibitor/MEK inhibitor targeted therapy was allowed).16 During induction, patients received the combination of nivolumab 1 mg/kg and ipilimumab 3 mg/kg for four cycles every three weeks, followed by nivolumab 3 mg/kg monotherapy every two weeks. At the time of the data cutoff for ASCO, 75 patients had been followed for a median of 9.2 months. Objective response rates for intracranial disease are shown in Figure 6A. The median time to response was 2.8 months, and the median duration of response had not been reached. Among the 41 patients who had responded, the response was ongoing in 36 (93%). This regimen was again shown to have a high toxicity rate: 52% of patients experienced at least one grade 3-4 AE, 25% discontinued due to an AE and one treatment-related death was reported (myocarditis).

The other study is the Anti-PD-1 Brain Collaboration (ABC) study, which included patients with brain metastases 0.5-4.0 cm and no previous exposure to immuno-oncologic agents.17 Those who were asymptomatic with no prior local therapy were randomized to receive nivolumab 3 mg/kg as monotherapy (n = 27) or the nivolumab + ipilimumab combination (regimen as above; n = 33). Sixteen additional patients were previously treated, or symptomatic or leptomeningeal, with MRI progression. These patients received nivolumab 3 mg/kg monotherapy. Response data for the first two groups in this interim analysis (median follow-up 16.4 months) are shown in Figure 6B. In terms of safety, 12 of the 26 patients in the combination arm experienced a grade 3-4 AE, all judged to be treatment related. Seven patients discontinued due to AEs. No overall survival data were presented for either study.

In the nivolumab studies described above, the ipilimumab dose was 3 mg/kg every 3 weeks. Given the toxicity of nivolumab + ipilimumab, the combination of pembrolizumab + lower-dose ipilimumab has been investigated among patients with advanced melanoma. At ASCO 2017, investigators presented updated efficacy and safety results from the phase 1, open-label, single-arm KEYNOTE-029 study, in which patients were treated with a combination of a standard dose of pembrolizumab and a lower dose of ipilimumab (1 mg/kg every 3 weeks).18 The rationale for the lower dose was the desire to retain the efficacy benefits of combination therapy while reducing the risk of serious AEs. The median follow-up for this updated analysis was 17.0 months. Over this period of time, the median PFS and OS were not reached. Estimated 12-month PFS was 69% and 12-month OS was 89%. There were a total of 69/153 patients (45%) with a treatment-related grade 3-4 AE. Forty-eight patients (31%) discontinued at least one study drug due to AEs; 22 patients (14%) discontinued both. No treatment-related deaths were reported.

In terms of combination therapy, there were also preliminary data reported in a study of multiple tumor types showing that combining nivolumab with varlilumab, an anti-CD27 agonist antibody, may be of clinical utility in patient populations expected to have minimal response to checkpoint blockade.18

Long-term data for targeted therapy also was presented at ASCO 2017. Researchers provided an update on OS at five years in a phase 2 study evaluating combination targeted therapy (dabrafenib + trametinib) in patients with BRAF V600-mutant metastatic melanoma.20 Patients were randomized to one of three groups: dabrafenib 150 mg bid + trametinib 2 mg od, dabrafenib 150 mg bid + trametinib 1 mg od; or dabrafenib 150 mg bid monotherapy. Median follow-up for the presentation at ASCO was 66.5 months. As shown in Figure 7, a survival plateau appears to have been established for combination targeted therapy in a minority of patients (approximately 30%), which has continued through the fifth year of follow-up. This suggests the potential for long-term stability among those who respond to combination targeted therapy. No new safety signals emerged in this analysis.

Finally, there were some intriguing immuno-oncology data presented in the adjuvant setting in melanoma. A phase 3 study evaluated the use of adjuvant ipilimumab or high-dose interferon (IFN) alpha-2b for resected, high-risk melanoma.21 A total of 1,673 patients were randomized to receive ipilimumab 3 mg/kg for induction and maintenance, ipilimumab 10 mg/kg for induction and maintenance, or an IFN regimen (IFN-α2b 20 MU/m2/d IV for one month for induction and 10 MU/m2 SC tiw x 11 months for maintenance). At ASCO 2017, results from an unplanned analysis were presented for the ipilimumab arms only and included a median follow-up of 3.1 years. Median recurrence-free survival was 3.9 years with the ipilimumab 10 mg/kg dose and not reached with the 3 mg/kg dose. The 3-year recurrence-free survival rate was 54% for ipilimumab 10 mg/kg and 56% for ipilimumab 3 mg/kg. The 10 mg/kg dose was associated with significantly greater toxicity than the 3 mg/kg dose. The proportion who discontinued due to a treatment-related AE was 53.7% for ipilimumab 10 mg/kg and 34.9% for ipilimumab 3 mg/kg. There were also eight treatment-related deaths in the 10 mg/kg arm (1.6%) and two in the 3 mg/kg arm (0.4%).

﻿EXPERT COMMENTARY - DR. TERESA PETRELLA
﻿Updated results from KEYNOTE-006 showed that 50% of patients were still alive at 32 months; and in another study with dabrafenib and trametinib, 30% of patients were still alive at five years. The group of patients that had good prognostic factors, such as low LDH, fewer disease sites and good ECOG, fared even better. These results confirmed longer-term survival in randomized trials and are reassuring for our patients. Data presented also confirmed that those who completed their two years of pembrolizumab were still doing well at almost 10 months of follow-up. These data are important for Canadian oncologists, as we can reassure our patients who have completed their therapy. What remains to be answered is 1) Is there a tail to the curve from immunotherapy and targeted therapy (I think we will need longer follow-up to answer this); and 2) How do we choose between targeted and immunotherapy in first line (currently there are ongoing trials that will hopefully answer this).

Brain metastases are a leading cause of morbidity and the leading cause of death for metastatic melanoma patients. Encouraging results were presented this year that highlight the possibility of new treatment options for our metastatic melanoma patients with brain metastases. Data from two phase 2 studies (CHECKMATE-204 and the ABC study) lend support to the use of the combination of nivolumab + ipilimumab, with intracranial response rates of 55%. However, grade 3-4 toxicity remained high at 53% and hence we will need to balance efficacy with toxicity. The main question that remains is whether we should be using combination nivolumab + ipilimumab to treat brain metastases. These were small, non-randomized studies, so the results should be confirmed in larger trials. These results also show that it is feasible to conduct clinical trials in brain metastases patients which will hopefully lead to more treatments being available for these patients.

Immuno-oncology in Urothelial Cancers

Immuno-oncologic agents also have been evaluated for the treatment of urothelial carcinoma (UC) with mixed results. Pembrolizumab was compared to second-line chemotherapy of choice in patients with UC who had progressed on first-line platinum-based chemotherapy in the KEYNOTE-045 study22 and demonstrated a significant improvement in OS and other endpoints. However, a similar phase 3 study with the PD-L1 inhibitor, atezolizumab, (IMvigor-211) had failed to meet its primary endpoint.23 At ASCO 2017, data were presented with pembrolizumab that further support continued investigation of immuno-oncology in UC.

The KEYNOTE-052 trial was a single-arm study that evaluated pembrolizumab as first-line treatment for 370 patients with advanced UC who were not eligible for cisplatin therapy.24 For the presentation at ASCO 2017, the median follow-up was 9.5 months. The objective response rate was 29% (108/370), including 27 patients (7%) with a complete response (Table 1). The median time to response was two months and the median duration of response was not reached. The investigators identified a threshold of ≥ 10% PD-L1 expression (by combined positive score [CPS]) as the optimal cut-off for predicting response to pembrolizumab. Those with a CPS ≥ 10% had an ORR of 51% in the validation set (n = 80) compared to 23% among those with a CPS < 10% (Table 1).

The impact of PD-1 inhibition on health-related quality of life also has been evaluated for each of pembrolizumab and nivolumab as second-line therapy for UC. In KEYNOTE-045,25 pembrolizumab was associated with significantly better quality of life outcomes compared to the chemotherapy comparator arm. Similarly, in the single-arm nivolumab study, CHECKMATE-275,27 patients treated with nivolumab after failing cisplatin-based therapy demonstrated either significantly improved or at least stable quality of life metrics while on therapy.

An updated survival analysis of KEYNOTE-045 also was presented at ASCO 2017.26 Median follow-up was 18.5 months and mortality was reduced by 30% (HR 0.70; p = 0.0004). OS at 12 months was 44.4% with pembrolizumab vs. 30.2% with chemotherapy; and at 18 months was 36.1% vs. 20.5%, respectively. Median response duration with pembrolizumab had not been reached. Among responders, responses lasting ≥ 12 months were seen in 69% with pembrolizumab and 36% with chemotherapy.

As for other disease types, efforts at improving efficacy through combination therapy are underway. As an example, the preliminary results of the phase 1/2 study of the combination of pembrolizumab + epacadostat (ECHO-202/KEYNOTE-037) were presented, which included 40 patients with UC.28 Epacadostat is an orally available hydroxyamidine and inhibitor of indoleamine 2, 3-dioxygenase (IDO1), with potential immunomodulating and antineoplastic activities. Over a median follow-up of 33.8 weeks, the overall ORR among these patients was 35% (14/40 patients), including three patients with a complete response. Median duration of response for this analysis was 30.6 weeks; 10/14 responses were ongoing.

﻿EXPERT COMMENTARY - DR. SEBASTIEN HOTTE
It is clear from a number of phase 1, 2 and 3 studies that stimulation of the immune system can achieve significant and lasting clinical improvements in a subset of patients with UC. Data presented at ASCO 2017 highlight the fact that these agents are usually well tolerated, may have a positive impact on quality of life, and may also significantly improve survival and probability of long-term survival (at least in patients treated with pembrolizumab). Although there may be several reasons for the disparate results observed in the KEYNOTE-045 and IMvigor-211, it is important to note two things. First, UC remains a chemosensitive malignancy and many patients (even post cisplatin) will respond to chemotherapy. Second, although some patients respond extremely well to PD-1 and PD-L1 inhibitors, many others do not respond at all. As a result, it is imperative to continue efforts to create tools that can help clinicians better delineate which patients are most likely to respond to immuno-oncologic therapy and which patients may be best treated with existing chemotherapy options or, optimally, entry into a clinical trial. Efforts to combine PD-1 or PD-L1 agents with chemotherapy or with other immune modulators are underway, and will hopefully lead to more robust and long-lasting efficacy results in the near future.

Discussion

The data presented at ASCO 2017 help to reinforce some key themes that had previously emerged in the field of immuno-oncology.

Not all agents are the same in terms of efficacy; the differences between the pembrolizumab and nivolumab trials in first-line therapy for NSCLC, updated at this meeting, serve to underline this observation. We cannot assume that positive findings with one agent in the class can be extrapolated to other agents with similar mechanisms of action. As the immuno-oncology trials progress in urothelial cancers (and potential other areas of oncology as well), clinicians and regulatory authorities will be watching to see if similar patterns emerge.

In terms of combination therapy with a PD-1 inhibitor and the CTLA-4 inhibitor, ipilimumab, the data presented at ASCO continue to show that a numerical OS efficacy advantage can be gained by combining these agents, but that one must make the recommendation on a case-by-case basis, as the significant additional toxicity of the combination may not be manageable for all patients.

Finally, identifying patients who are candidates for immuno-oncology continues to be a work in progress. While the 50% threshold of PD-L1 expression is solidly evidence-based for pembrolizumab in NSCLC, research presented at ASCO 2017 suggests that a 10% threshold is most reasonable for urothelial cancer. In the context of limited access to these medications, evidence-based thresholds are important components of the decision-making process regarding who will receive these agents and who will not.

Ongoing research will continue to sharpen the focus on these and other issues as the field of immuno-oncology continues to evolve.

27. Health-related quality of life as a marker of treatment benefit with nivolumab in platinum-refractory patients with metastatic or unresectable urothelial carcinoma from CheckMate 275. Presented at ASCO 2017; abstract 4526.

Copyright 2017 STA HealthCare Communications Inc. All rights reserved. Development of this article was made possible through the financial support of Merck Canada Inc. The opinions expressed herein are those of the authors, and do not necessarily reflect the views and opinions of Merck Canada Inc. The authors had complete editorial independence in the development of this article and are responsible for its accuracy. The sponsor exerted no influence in the selection of content or material published.